Current Drug Discovery Technologies (v.7, #4)

Cancer is an important health problem in the Developed World where it is the second cause of death, mainly associated with ageing of the population and lifestyle. Along with surgery and chemotherapy, radiation therapy (radiotherapy) is one of the most important tools to combat cancers. More than half of all cancer patients will receive radiotherapy at some stage during the course of their illness [1]. The goal of radiation therapy is to deliver a precisely measured dose of ionizing radiation to a defined tumor area, with as little damage as possible to surrounding healthy, non-cancerous tissue [2]. However, most types of radiation do not attack cancer cells specifically, and therefore cause injury to normal tissues surrounding the tumor. Therefore, a number of patients undergoing radiation therapy will experience a range of side effects, which may lead to an interruption of treatment or limiting the dose of radiation [3]. These adverse effects are a major factor limiting the success of radiation treatment. Considerable research activity is focused on improving radiotherapy outcome and reducing adverse effects. As radiotherapy aims to deliver the necessary therapeutic dose of ionising radiation to tumour tissue whilst minimizing irradiation of normal tissue, precise tumour volume delineation is essential. It is in this setting that the role of PET in the radiotherapy management of patients has been investigated. Indeed, PET offers additional advantages over CT as it can provide both anatomical and biological tumour information. For example, by detailing and quantifying tumour metabolism, hypoxia and perfusion, tumour delineation can be improved and a more refined target can be identified [4]. Although the above strategies can be implemented, radiotherapy is still limited by the tumor volume or the surrounding normal tissue tolerance to radiation. Recent advances in molecular biology has created a novel framework that can improve clinical practice considerably. The identification of cellular receptors, enzymes, and pathways involved in tumorgeneity has resulted in the development of biologically targeted drugs. Also the fact that cancer cells need their microenvironment has opened the door to new therapeutic strategies which can expand radiotherapy practice. Fifty years ago, targeted radiotherapy started with the use of 131I-NaI therapy for thyroid cancer and even up to today, this is the only targeted radiotherapy based approach that is approved by the U.S. Food and Drug Administration [5]. Twenty years later, treatment of metastatic bone pain using bone-seeking radiopharmaceuticals such as 153Sm, 89Sr, and 186Re has become an important tool in clinical practice. Indeed, the incidence of bone metastases is very high and bone secondaries are a common cause of cancer pain [6]. More recently, targeted radiotherapy has become more sophisticated through the use of radiolabelled microspheres and antibodies and by targeting the cell nucleus. This collection of reviews on targeted radionuclide therapy provides a snapshot of the current status of modern clinical applications of therapeutic nuclear medicine.

Targeted Radiotherapy of Bone Malignancies by David R. Jansen, Gerard C. Krijger, Zvonimir I. Kolar, Bernard A. Zonnenberg, Jan Rijn Zeevaart (233-246).
The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as 89Sr or 223Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [153Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (and#946;-) emitters: 153Sm, 89Sr, 186Re, 188Re, 32P, 177Lu and 170Tm; alpha (and#945;) emitters: 223Ra and 225Ra; and Auger or conversion electron emitter: 117mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting 99mTc, and positron emitters 18F and 68Ga. The current status in the development and application of internal radiotherapy for the palliative treatment of bone pain will be discussed, summarizing the progress made and challenges encountered in the process to realizing an effective drug candidate.

Radioembolization of Hepatocellular Carcinoma by Christophe Van de Wiele (247-252).
In this review paper, available data on radioembolization of unresectable hepatocellular carcinoma (HCC) using commercially available radiopharmaceuticals, respectively 131I-Lipiodol, Therasphere (glass-microspheres) and SIRspheres (resin-microspheres) are reviewed. In the palliative setting, 131I-Lipiodol was shown to yield response rates of 17- 92and#x25; which in patients with portal vein thrombosis (PVT) translate into a survival benefit as evidenced by a phase III randomized trial. Furthermore, in terms of efficacy, 131I-Lipiodol is as efficacious as trans-arterial chemoembolization (TACE) but far better tolerated. In the adjuvant setting, improved recurrence-free and overall survival when compared to surgery alone have been reported but these results warrant confirmation by randomized prospective trials. Similar to 131I-Lipiodol, when administered in a palliative setting, radioembolization using 90Y microspheres was proven effective for selected cases of non-resectable HCC and well tolerated. Available data suggest that Therasphere treatment outperforms TACE both in terms of response as in terms of event-free survival in unresectable HCC. However, this finding needs confirmation by randomized prospective trials. Therasphere treatment was also shown to limit progression of HCC allowing potential candidates for orthotopic liver transplantation (OLT) more time to wait for donor organs as well as to downstage the HCC disease to such an extent that patients that were initially not, as yet become eligible for OLT with a gain in survival. Finally, Therasphere was shown to be safe and efficacious in HCC patients presenting with PVT, reason for which approval was granted for this indication by the FDA.

Current Concepts and Future Directions in Radioimmunotherapy by Frank I. Lin, Andrei Iagaru (253-262).
Radioimmunotherapy relies on the principles of immunotherapy, but expands the cytotoxic effects of the antibody by complexing it with a radiation-emitting particle. If we consider radioimmunotherapy as a step beyond immunotherapy of cancer, the step was prompted by the (relative) failure of the latter. The conventional way to explain the failure is a lack of intrinsic killing effect and a lack of penetration into poorly vascularized tumor masses. The addition of a radioactive label (usually a and#946;-emitter) to the antibody would improve both. Radiation is lethal and the type of radiation used (beta rays) has a sufficient range to overcome the lack of antibody penetration. At present, the most successful (and FDA approved) radioimmunotherapy agents for lymphomas are anti-CD20 monoclonal antibodies. Rituximab (Rituxanand#174;) is a chimeric antibody, used as a non-radioactive antibody and to pre-load the patient when Zevalinand#174; is used. Zevalinand#174; is the Yttrium-90 (90Y) or Indium-111 (111In) labeled form of Ibritumomab Tiuxetan. Bexxarand#174; is the Iodine-131 (131I) labeled form of Tositumomab. Ibritumomab Tiuxetan and Tositumomab are murine anti-CD20 monoclonal antibodies, not chimeric antibodies. Promising research is being done to utilize radioimmunotherapy earlier in the treatment algorithm for lymphoma, including as initial, consolidation, and salvage therapies. However, despite more than 8 years since initial regulatory approval, radioimmunotherapy still has not achieved widespread use due to a combination of medical, scientific, logistic, and financial barriers. Other experimental uses for radioimmunotherapy include other solid tumors to treat infections. Optimization can potentially be done with pre-targeting and bi-specific antibodies. Alpha particle and Auger electron emitters show promise as future radioimmunotherapy agents but are mostly still in pre-clinical stages.

Targeting the Nucleus: An Overview of Auger-Electron Radionuclide Therapy by Bart Cornelissen, Katherine A Vallis (263-279).
The review presented here lays out the present state of the art in the field of radionuclide therapies specifically targeted against the nucleus of cancer cells, focussing on the use of Auger-electron-emitters. Nuclear localisation of radionuclides increases DNA damage and cell kill, and, in the case of Auger-electron therapy, is deemed necessary for therapeutic effect. Several strategies will be discussed to direct radionuclides to the nucleoplasm, even to specific protein targets within the nucleus. An overview is given of the applications of Auger-electron-emitting radionuclide therapy targeting the nucleus. Finally, a few suggestions are made as how radioimmunotherapy with nuclear targets can be improved, and the challenges that might be met, such as how to perform accurate dosimetry measurements, are examined.

Efforts to develop an effective malarial vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Unfortunately, Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to classical antimalarials, necessitating a search for new chemotherapeutics preferably with novel modes of action. Today, rational drug discovery strategy is gaining new impetus as knowledge of malaria parasite biology expands, aided by the parasite genome database and improved bioinformatics tools. Drug development is a laborious, time consuming and costly process, and thus the and#x201C;useful therapeutic livesand#x201D; (UTLs) of new drugs should be commensurate with the resources invested in their development. Historical evidence on development and evolution of resistance to classical antimalarial drugs shows that the mode of action of a drug influences its UTL. Drugs that target single and specific targets such as antimalarial antifolates and atovaquone (ATQ) are rendered ineffective within a short time of their clinical use, unlike drugs with pleiotropic action such as chloroquine (CQ) and artemisinins (ART) with long UTLs. Unfortunately, almost all new targets currently being explored for development of novel drugs belong to the and#x201C;specific targetand#x201D; other than the and#x201C;multiple targetand#x201D; category, and is plausible that such drugs will have short UTLs. This review relates the pleiotropic action of CQ and ART with their long UTLs, and discusses their relevance in rational drug development strategies. Novel targets with potential to yield drugs with long UTLs are also explored.